Nuclear Respiratory Factor 1 Promotes The Growth of Liver Hepatocellular Carcinoma Cells Via E2F1 Transcriptional Activation

Abstract

Background Recent studies have shown that functional mitochondria are essential for cancer cells. Nuclear respiratory factor 1 (NRF1) is a transcription factor that activates mitochondrial biogenesis and the expression of the respiratory chain, but little is known about its role and underlying mechanism in liver hepatocellular carcinoma (LIHC). Methods NRF1 expression was analyzed via public databases and 24 paired LIHC samples. Clinical-pathological information and follow-up data were collected from 165 patients with LIHC or online datasets. Furthermore, cellular proliferation and the cell cycle were analyzed by MTT, Clone-forming assay and flow cytometric analyses. NRF1 target genes were analyzed by Chromatin immunoprecipitation sequencing (ChIP-Seq). PCR and WB analysis was performed to detect the expression of related genes. ChIP and luciferase activity assays were used to identify NRF1 binding sites.Results Our results showed that NRF1 expression was upregulated in LIHC compared to normal tissues. NRF1 expression was associated with tumour size and poor prognosis in patients. Knockdown of NRF1 repressed cell proliferation, and overexpression of NRF1 accelerated the G1/S phase transition. Additionally, data from ChIP-seq pointed out that some NRF1 target genes are involved in the cell cycle. Our findings indicated that NRF1 directly binds to the E2F1 promoter as a transcription factor and regulates its gene expression. Conclusion Therefore, this study revealed that NRF1 promotes cancer cell growth via the indirect transcriptional activation of E2F1 and is a potential biomarker in LIHC.

Association of mitochondrial homeostasis and dynamic balance with malignant biological behaviors of gastrointestinal cancer

“…Some lncRNAs were found to form complex with NRF1 to activate mitochondrial biogenesis in HCC [55] and colorectal cancer patients [56]. NRF1 was also found to activate E2F1 as a transcription factor to promote HCC proliferation by a ChIP-seq analysis for NRF1 target genes [57]. Similarly, the knock-down of TFAM could promote cancer progression according to bioinformatic databases of 18 head and neck cancer cases [58] as well as ovarian cancer [59].…”